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MS 02 - Ethnic Differences: Biology or Myth (ID 524)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Regional Aspects/Health Policy/Public Health
- Presentations: 1
MS 02.03 - Chemotherapy: Efficacy and Toxicity Difference According to Ethnicity (ID 7729)
11:00 - 12:30 | Presenting Author(s): Martin Edelman
Despite advances in immunotherapy and targeted therapies for lung cancer, cytotoxic chemotherapeutic agents remain the backbone of therapy for most patients. There has long been evidence that different populations demonstrate differential sensitivity and toxicity to chemotherapy agents. With the increasing globalization of trials, understanding and adjusting for these differences will be of increasing importance for the development of new agents as well as the safe and effective use of existing drugs. Mechanisms of differential toxicity/efficacy Different populations may experience altered safety profiles. Differential toxicity is not surprising as different populations demonstrate variability in detoxifying liver enzymes (e.g.cytochrome P450). Depending upon the drug, this could alter metabolism to an active agent or to an inactive compound. Metabolism can also affect aspects of drug clearance. Differential efficacy could be the result of several factors. Altered metabolism or clearance (as discussed above) may result in greater exposure of the tumor to active agent. Alternatively, accelerated metabolism/clearance could result in less exposure and potentially less activity. Another, less well appreciated aspect, is the different incidence of activating mutations in the populations, such as EGFR or ALK. Dietary differences may also alter metabolism and activity. Some of this is due to regulatory requirements. For example, the United States requires folate supplementation of bread and many other products to prevent congenital neural tube defects. This is not required in the European Union. Pemetrexed toxicity is significantly impacted by folate repletion and as early development in the EU demonstrated that additional folate obviated rash and led to the requirement for folate supplementation. It is possible that this has resulted in over supplementation in the US. Conversely, capecitabine becomes more toxic (and possibly more effective) in folate replete patients. Trial evidence for differential toxicity/efficacy Observed differences in efficacy could potentially be due to differences in entry criteria, study execution etc. Investigators in the United States (Southwest Oncology Group, SWOG) and Japan addressed these issues through a series of “common arm” trials in small cell (SCLC) and non-small cell lung cancer (NSCLC). Trials comparing cisplatin/etoposide with cisplatin/irinotecan were conducted in Japan (J9511) and the United States (S0124). A retrospective analysis of patient level data was undertaken. Drug doses, eligibility criteria, assessments and analysis were similar between the two studies. There were significant differences in toxicity and efficacy. Both cisplatin/etoposide and cisplatin/irinotecan demonstrated greater hematologic toxicity in the Japanese. In terms of efficacy, cisplatin/etoposide demonstrated higher response rate, but similar survival endpoints. In contrast, cisplatin/irinotecan demonstrated a higher response rate, progression free and overall survival in the Japanese vs. US population. An analysis of the US trial demonstrated significant associations of GI and hematologic toxicity with ABCB1 (Odds Ratio, OR: 3.9) and UGT1A1 (OR: 24) polymorphisms, respectively. A prospective “common arm” study was undertaken in the NSCLC setting by the same groups. In this case, the common arm was carboplatin/paclitaxel. Once again there were significant differences in terms of both toxicity and activity. In this prospective study, the investigators obtained information regarding germline CYP and DNA repair enzymes. There were significant differences between patients from Japan and the USA in genotype distribution for CYP3A4*1B (p = 0.01), CYP3A5*3C (p = 0.03), ERCC1 118 (p < 0.0001), ERCC2 K751Q (p < 0.001) and CYPC28*3 (p = 0.01). Mutational status may influence response to chemotherapy and there are clear geographic variations for some driver mutations. The incidence of activating mutations of EGFR is approximately 10% in Western countries but >25% in many Asian countries. In addition to predicting outcome for EGFR tyrosine kinase inhibitors (TKIs), EGFR mutations also convey greater sensitivity to cytotoxic chemotherapy. In the IPASS study, the response rate for carboplatin/paclitaxel was 47% vs. 23.5% for mutation positive vs. negative patients. Given the much greater number of patients with EGFR mutation related NSCLC in Asia, this is likely a major source of discrepancy in outcomes. Interestingly, mutational status may also influence the degree of benefit from different chemotherapy agents. In a phase III trial comparing chemotherapy to crizotinib in patients with ALK translocated disease, patients could receive either pemetrexed or docetaxel as their chemotherapy. The HR for crizotinib vs pemetrexed was .59 while it was .30 for patients receiving docetaxel. Summary The past 20 years has seen significant progress in our understanding of lung cancer. It is now common to declare that there are many different lung cancers and to focus on susceptibility to targeted or immunotherapy based upon tumor characteristics. It is critical that in this era we not lose sight of the fact that there is still significant potential to improve outcomes with older chemotherapy agents, both in terms of toxicity and efficacy, based upon better understanding and utilization of both germline and tumor characteristics. Insights gained from evaluations of different ethnic groups can guide these evaluations. Suggested Reading Edelman MJ, Sekine I, Tamura T, Saijo N. Geographic variation in the second-line treatment of non-small cell lung cancer. Semin Oncol. 2006 Feb;33(1 Suppl 1):S39-44 Gandara DR, Kawaguchi T, Crowley J, Moon J, Furuse K, Kawahara M, Teramukai S, Ohe Y, Kubota K, Williamson SK, Gautschi O, Lenz HJ, McLeod HL, Lara PN Jr, Coltman CA Jr, Fukuoka M, Saijo N, Fukushima M, Mack PC. Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics. J Clin Oncol. 2009 Jul 20;27(21):3540-6. Lara PN Jr, Chansky K, Shibata T, Fukuda H, Tamura T, Crowley J, Redman MW, Natale R, Saijo N, Gandara DR. Common arm comparative outcomes analysis of phase 3 trials of cisplatin + irinotecan versus cisplatin + etoposide in extensive stage small cell lung cancer: final patient-level results from Japan Clinical Oncology Group 9511 and Southwest Oncology Group 0124.Cancer. 2010 Dec 15;116(24):5710-5. Mack PC, Gandara DR, Lara PN. Efficacy and toxicity differences in lung cancer populations in the era of clinical trials globalization: the ‘common arm’ approach Expert Rev. Anticancer Ther. 12(12), 1591–1596 (2012) Mok TS1, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Saijo N. The Role of Pharmacoethnicity in the Development of Cytotoxic and Molecular Targeted Drugs in Oncology Yonsei Med J 5: 1-14, 2013 Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94.
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OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
OA 14.07 - Progress in Lung Squamous Cell Carcinoma from the Lung-MAP Master Protocol (S1400) Sub-Studies S1400A, S1400B, S1400C and S1400D (ID 9593)
11:00 - 12:30 | Author(s): Martin Edelman
Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study.
Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response.
As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table.
Sub-study Final Accrual Biomarker prevalence/% of sub-study registrations Closure Date Response to investigational therapy N (%) Status S1400A (non-match) Total: 116 Durvalumab: 78 Docetaxel: 38 NA/59% 12/18/15 Docetaxel arm closed: 4/22/15 11 (16%) Administratively closed to enable activation of new non-match study. S1400B PI3K Total: 39 taselisib: 31 Docetaxel: 8 8%/9% 12/12/16 Docetaxel arm closed: 12/18/15 1 (4%) Closed at interim futility analysis. S1400C (CCGA+) Total: 54 Palbociclib: 37 Docetaxel: 17 19%/15% 09/01/16 Docetaxel arm closed: 12/18/15 2 (6%) Closed at interim futility analysis. S1400D (FGFR+) Total: 45 AZD4547: 35 Docetaxel: 10 16%/12% 10/31/16 Docetaxel arm closed: 12/18/15 2 (7%) Closed at interim futility analysis. S1400E (MET+) Total: 9 R+E: 4 E: 5 N/A (closed too early) 11/26/2014 N/A Closed d/t discontinuation of development of rilotumumab
Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.